Combined Iron Chelator and Antioxidant Exerted Greater Efficacy on Cardioprotection Than Monotherapy in Iron-Overloaded Rats.

Iron chelators are used to treat iron overload cardiomyopathy patients. However, a direct comparison of the benefits of three common iron chelators (deferoxamine (DFO), deferiprone (DFP) and deferasirox (DFX)) or an antioxidant (N-acetyl cysteine (NAC)) with a combined DFP and NAC treatments on left ventricular (LV) function with iron overload has not been investigated.Male Wistar rats were fed with either a normal diet or a high iron diet (HFe group) for 4 months. After 2 months, the HFe-fed rats were divided into 6 groups to receive either: a vehicle, DFO (25 mg/kg/day), DFP (75 mg/kg/day), DFX (20 mg/kg/day), NAC (100 mg/kg/day) or the combined DFP and NAC for 2 months. Our results demonstrated that HFe rats had increased plasma non-transferrin bound iron (NTBI), malondialdehyde (MDA), cardiac iron and MDA levels and cardiac mitochondrial dysfunction, leading to LV dysfunction. Although DFO, DFP, DFX or NAC improved these parameters, leading to improved LV function, the combined DFP and NAC therapy caused greater improvement, leading to more extensively improved LV function.The combined DFP and NAC treatment had greater efficacy than monotherapy in cardioprotection through the reduction of cardiac iron deposition and improved cardiac mitochondrial function in iron-overloaded rats

The summary of the experimental protocol.

<p>ND = normal diet group; HFe = high iron diet group; V = vehicle; DFO = deferoxamine; DFP = deferiprone; DFX = deferasirox; NAC = N-acetyl cysteine; NTBI = non-transferrin bound iron; MDA = malondialdehyde; ROS = reactive oxygen species; ΔΨ_m = membrane potential change.</p

The effects of the pharmacological interventions on blood pressure parameters in iron-overloaded rats.

<p>The effects of the pharmacological interventions on blood pressure parameters in iron-overloaded rats.</p

Diagram illustrating the proposed mechanisms of chronic iron overload on cardiac dysfunction and the effects of all pharmacological interventions on cardiac dysfunctions caused by chronic iron overload.

<p>Dashed arrows indicate the effects of either DFO, DFP, DFX or NAC treatment; solid arrows indicate the effects of combined DFP plus NAC treatment. DFO = deferoxamine; DFP = deferiprone; DFX = deferasirox; NAC = N-acetyl cysteine; NTBI = non-transferrin bound iron; MDA = malondialdehyde.</p

The effects of the pharmacological interventions on hemodynamic parameters in iron-overloaded rats.

<p>The effects of the pharmacological interventions on hemodynamic parameters in iron-overloaded rats.</p

Chronic iron overloaded impaired heart rate variability and decreased cardiac function in iron-overloaded rats.

<p>The effects of the iron overload condition on: (A) heart rate variability at baseline, 2, 3 and 4 months, and (B) the percentage of left ventricular fractional shortening (%LVFS) measured using echocardiography at baseline, 2, 3 and 4 months in iron-overloaded rats. *<i>P</i> < 0.05 vs. control, †<i>P</i> < 0.05 vs. HFe diet for 2 months, ‡<i>P</i> < 0.05 vs. HFe diet for 3 months.</p

Combined DFP+NAC treatment could decrease plasma NTBI and MDA levels as well as restore normal cardiac iron and MDA content in iron-overloaded rats.

<p>The effects of the pharmacological interventions on: (A) plasma non-transferrin bound iron (NTBI) level; (B) plasma malondialdehyde (MDA) content; (C) cardiac iron concentration and (D) cardiac MDA content in iron-overloaded rats. *<i>P</i> < 0.05 vs. control, †<i>P</i> < 0.05 vs. HFe, ‡<i>P</i> < 0.05 vs. HFeDFP+NAC.</p

Electron micrographs of cardiac mitochondria from control, HFeV, HFeDFO, HFeDFP, HFeDFX, HFeNAC and HFeDFP+NAC groups.

<p>Iron-overloaded rats led to dysmorphic morphology and swelling of cardiac mitochondria compared to the control group. All of the pharmacological interventions could restore cardiac mitochondrial morphology which was obtained by using a transmission electron microscope in iron-overloaded rats.</p